title: Hepatitis C virus immune escape via exploitation of a hole in the T cell repertoire.
abstract: Hepatitis C virus (HCV) infection frequently persists despite eliciting substantial virus-specific immune responses. Thus, HCV infection provides a setting in which to investigate mechanisms of immune escape that allow for viral persistence. Viral amino acid substitutions resulting in decreased MHC binding or impaired Ag processing of T cell epitopes reduce Ag density on the cell surface, permitting evasion of T cell responses in chronic viral infection. Substitutions in viral epitopes that alter TCR contact residues frequently result in escape, but via unclear mechanisms because such substitutions do not reduce surface presentation of peptide-MHC complexes and would be expected to prime T cells with new specificities. We demonstrate that a known in vivo HCV mutation involving a TCR contact residue significantly diminishes T cell recognition and, in contrast to the original sequence, fails to effectively prime naive T cells. This mutant epitope thus escapes de novo immune recognition because there are few highly specific cognate TCR among the primary human T cell repertoire. This example is the first on viral immune escape via exploitation of a "hole" in the T cell repertoire, and may represent an important general mechanism of viral persistence.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wölfl
authors.forename: Alleluiah
authors.initials: A
authors.lastname: Rutebemberwa
authors.forename: Timothy
authors.initials: T
authors.lastname: Mosbruger
authors.forename: Qing
authors.initials: Q
authors.lastname: Mao
authors.forename: Hong-mei
authors.initials: HM
authors.lastname: Li
authors.forename: Dale
authors.initials: D
authors.lastname: Netski
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Ray
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Todd
authors.initials: T
authors.lastname: Allen
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuntzen
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Kavanagh
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kuball
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Cox
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D017951:Antigen Presentation / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D006801:Humans; D009154:Mutation; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism; D017735:Virus Latency / Q000276:immunology*; D055815:Young Adult
chemical_list: D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins